The Eukaryotic Linear Motif resource for
Functional Sites in Proteins

ELM candidate motifs

ELM annotation process is a tedious and time-consuming process involving critical reading of primary and secondary literature, finding motif instances, generating multiple sequence alignments and more. In order not to loose track of possible annotations, we keep the following list of candidate motifs.
We invite researchers to send us their feedback and expert opinion on these classes and to contribute novel motif classes that will be added to the candidate page and ultimately be turned into full ELM classes. Minimum requirements are at least one literature reference as well as a short description. In addition, a draft regular expression or a 3D structure showing the relevant interaction would also be helpful.

Currently 84 candidates need annotation: (Add a new candidate)

Detailed Status:
fully annotated: 84
Identifier Model References Description Notes Status
LIG_Vh1_VBS_1 ([IL][VILY].[^P]A[^P].[VIL][^P].[^P][VLMT][^P][^P][VL][VIL])|(DD[IL][VILY].[^P]A[^P].[VL][^P].[^P][VLM][^P]P[VL][VIL]) Izard,2004 Crystal structure of the VBS-N in Talin 1 with Vh1 from Vinculin.

22334306 The second alpha-helix in Talin 1 (VBS-C) binds to Vh1 in Vinculin.

Izard,2004 Talin 1 from Gallus gallus opens/activates human Vinculin.

Gingras,2006 Spot-peptide arrays to determine which positions that are or are not allowed in the binding VBS. Structures different helices in Talin in complex with Vh1 from Gallus gallus.

Gingras,2005 Crystal structure of Talin 1 from Gallus gallus with Vh1 from Gallus gallus.

Izard,2006 IpaA from Shigella flexneri contains two VBS motifs that bind in a mutually exclusive fashion to human Vinculin.

Hamiaux,2006 IpaA from Shigella flexneri contains two VBS motifs that bind simultaneously to two Vh1 domains from Vinculin.

Park,2011 VBS N and C terminal in sca4 from Rickettsia rickettsii.
Vinculin works as a linker that strengthens the association of Talin and F-Actin at sites of integrin activation allowing stronger actin binding and major stability of the sites of focal adhesion (23719537). Talin contains a small globular head and a long tail containing 63 predicted alpha helices. Apparently, some of these helices can form a tertiary structure when not activated, as shown by NMR experiments (Gingras,2006). After a substantial change in this tertiary structure, 11 out of the 63 helices are able to bind to Vh1 head domain of Vinculin, forming a helix bundle, as demonstrated by SPOT peptide analysis and crystallographic structures (Gingras,2006), the helical motif that allows the binding is referred as Vinculin Binding Site (VBS).

Interestingly, bacterial pathogens like Shigella flexneri and Rickettsia have developed mimic structures that resemble the architecture of the VBSs in Talin with the same biological function and co-localization with Talin that can induce actin polymerization without the need of integrin activation (Izard,2006; Hamiaux,2006; Park,2011).
The current regular expression matches some but not all the peptides that were confirmed as binders in a SPOT peptide analysis (Gingras,2005). In particular, it matches the one helix that has a crystal structure (1ZW2) demonstrating the binding but that it is unexpected to be a real one since it covers the binding site for the F-actin. A crystal structure (1ZVZ) showed that helix having a Met at the +1 position can bind Vh1 from Vinculin but after major changes in the side chains and the orientation of one alpha helix in Vh1. This Met in the +1 position was shown to impair the binding of VBS1 on a SPOT-peptide substitution array. Therefore, the current regular expression do not allows a Met in the +1 position.
Positions +4, +6, +9, +11 and +13 do not allow a Pro based on the SPOT-peptide substitution array. Position +14 allows a Pro when two Asp are present at position -2 and -1.
fully annotated
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LIG_GBD_Chelix_1 [ILV][VA][^P][^P][LI][^P][^P][^P][LM] Kim,2000 NMR structure of autoinhibited human WASP (1EJ5).
Peterson,2004 NMR structure of human WASP with a small molecule inhibitor (1T84).
Alto,2007 EspF from EPEC can bind to N-WASP as proved by coimmunoprecipitation assays and in vitro Arp2/3 activation. They measured the Kd for EspF and mini-N-WASP/Arp2/3 =11.8 nM.
Cheng,2008 EspFU activates WASP (NMR structure 2K42).
Sallee,2008 Alanine scan in rat N-WASP and human WASP and defined the main contacting residues. Effect on multiple binding of the repeats in EspFU.
Aitio,2012 NMR structure of the 3-proteins complex: human N-WASP, the SH3 domain of human IRTKS (aka BAIAP2L1) and one repeat of EspFU (2LNH).
Okrut,2015 Nck1 contains the C-helix that competes with the C-helix in the VCA segment when WASP is in its autoinhibited state.
WASP and N-WASP proteins are required to initiate actin nucleation by activating actin-related protein (ARP)2/3 complex. WASP/N-WASP contains a GTPase-binding domain (GBD) at the N-terminus and a verprolin-homology, connector-helix, acidic motif (VCA) (also referred to as WCA as the V region is also called WH2) segment at the C-terminus. Under basal conditions the C-helix motif fits in the GBD domain closing the protein and preventing its nucleation promoting function (Kim,2000). Three factors participate in coordination to activate N-WASP in the membrane, a GTPase like CDC42 that binds the GBD domain, an acidic phospholipid like PtdIns(4,5)P2 and a SH3-domain-containing protein (like Nck) that binds to the PxxP motifs located between the GBD and the VCA segments (Abdul-Manan,1999; Rohatgi,2001; Okrut,2015). Nck can get a membrane localization by using its SH2 domain to bind to phosphorylated tyrosine-containing proteins like Nephrin that is a transmembranal protein. The co-localization of Nck and N-WASP allows the C-helix motif located in the linker space of the first and the second SH3 domains to bind to the GBD domain, out competing with the intramolecular C-helix in N-WASP. Additional bindings between N-WASP and Nck can occur due to interactions between the PxxP motifs in N-WASP and the second and third SH3 domains in Nck Okrut,2015.

Interestingly, the effector proteins EspF and EspFU from the human pathogens Enterohaemorrhagic and Enteropathogenic Escherichia coli are able to activate WASP/N-WASP by using a mimic of the C-helix motif that is present in multiple copies, three in the case of EspF and between five and seven for EspFU (Alto,2007; Cheng,2008; Sallee,2008). The motif is conserved in homologous proteins from Citrobacter rodentium, a mouse enteric bacterium. The actin polymerization activating potency is higher in the pathogenic proteins due to a multiple binding of the repeats, increasing the density of activated N-WASP molecules (Sallee,2008).
Position +1: Ile in WASP, WASL, NCK and EspF; Leu in WASP, NCK and EspF; Val in EspFU
Position +2: Val in WASP, WASL and NCK; Ala in EspF and EspFU
Position +3: Gly in WASP and WASL; Lys in NCK; Gln in EspF and EspFU
Position +4: Ala in WASP, WASL and EspF; Asn in NCK; Arg in EspFU
Position +5: Leu in all except in some fish (Iso)
Position +6: Met in WASP and WASL; Lys in NCK and EspF; Iso, Met and Val in any repeat in EspFU (7 Iso; 76 Met; 54 Val)
Position +7: Different in WASP and EspF; Glu in WASL; Asp in NCK; Gln in EspFU
Position +8: Val in WASP and WASL; Thr in NCK; His in EspFU
Position +9: Met in WASP and WASL; Leu in NCK, EspF and EspFU

A regular expression based on occurrence of instances would be the following:
[ILV][VA][^P][^P][LI][IMVK][^P][HTV][LM]
fully annotated
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LIG_IBAR_NPY_1 NPY Campellone,2006 The binding site in Tir to induce EspFU-dependent actin assembly was mapped to a 12 aas region which is necessary and sufficient to recruit EspFU and initiate actin pedestal formation.

Brady,2007 Defined the motif NPY as responsible for pedestal formation when present in a Tir protein (either EHEC or EPEC). Its function is EspFU-dependent.

Weiss,2009 IRSp53 links the enterohemorrhagic E. coli effectors Tir and EspFU for actin pedestal formation.

Vingadassalom,2009 IRTKS links the EHEC actin assembly effectors Tir and EspF(U) during pedestal formation. WASP, EspFU and IRTKS-SH3 domain forms a complex.

de Groot,2011 Got the structure of EHEC Tir and the I-BAR domains of IRSp53 (2YKT). All residues contacting the NPY motif are conserved in IRSp53 and IRTKS.
Some pathogens have developed infection mechanisms that hijack host cell signalling so that they can extend their survival and satisfy their metabolic needs. Enterohemorrhagic Escherichia coli (EHEC) and Enteropathogenic E. coli (EPEC) interfere with the regulation of actin polymerization to ultimately form an actin pedestal that probably increases the contact area between the infected cell and the bacteria.

To do so, two slightly different mechanisms are used by EHEC and EPEC. Initially, the translocated intimin receptor (Tir) is traslocated by the type III secretrion system (T3SS). The Tir protein contains one globular cytoplasmic N-terminal domain that is dispensable for the pedestal formation but regulates its length (Campellone,2006), one central and extracellular domain that mediates binding to the bacterial intimin protein and a C-terminal domain that differs in the different pathovars. EPEC Tir contains a short insertion around Tyr 474 that is phosphorylated by host cell kinases and works as a binding motif (LIG_SH2_SRC) for the SH2 domain in Nck proteins. Nck, recruited to the plasma membrane and in particular close to the bacterial attachment site, activates N-WASP by using its LIG_GBD_Chelix_1 motif to bind to the GBD domain of N-WASP. The VCA regions can, then, activate Arp2/3 and initiate actin polimerization leading to pestestal formation.

EHEC Tir lacks the Nck binding property, instead, it sequesters and activates N-WASP by a ternary complex that includes a second effector protein, EspFU, and the host proteins IRSp53 or IRTKS. EHEC Tir uses the NPY motif located at the C-terminal domain to bind to the I-BAR domain of IRSp53/IRTKS (Campellone,2006; Brady,2007; Weiss,2009; Vingadassalom,2009; de Groot,2011). IRSp53/IRTKS has an SH3 domain that interacts with the multiple LIG_SH3_3 motif in EspFU. EspFU, in addition, has a LIG_GBD_Chelix_1 that mimics the same motif in Nck then converging in the activation of actin polymerization and pedestal formation with EPEC.
Based on the alignment of EHEC Tir proteins, the Ala at position +4 is conserved in EHEC Tir and EPEC Tir homologs as well as in putative intimin receptors in Edwarsiella and not in Lactobacilus aquaticus that has a Val at +4.
The Ala at position +4 faces opposite to the I-BAR domain in the 2YKT structure.

Position -1 is not conserved and varies in homologs (Val EHEC, D/E EPEC).

Position -2 has a conserved Val in all Escherichia spp. homologs and a Leu in Edwardsiella homologs. The Val fits in a non-hydrophobic pocket. Mutation of this Val to Ala did not affect pedestal formation (Brady,2007). The pocket is made by Arg114 and Tyr115.

Supplementary Table 3 from de Groot (de Groot,2011) contains possible NPY-containing interactors of I-BAR:
Only LIMK1 and LIMK2 had Val in position -2. Only MYO15 had Ala in position +4.
These proteins matched with the MEME logo generated with the EHEC and EPEC Tir homologs and putative intimin receptors: ITSN1, ITSN2 and SHAN2 (SHANK2).
fully annotated
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LIG_MLH1_MIPbox_1 ..S[rk][FY][F] Gueneau,2013,
Boehm,2016,
Dherin,2009,
4FMO,
4FMN
The MIP Box is found in repair and meiotic proteins including BLM, Ntg2, and Sgs1 that bind to the MLH1 component of MutL. The motif is recognised by the C-terminal domain of MLH1.
The MIP Box has a core aromatic doublet and also has a preference for basic residues. These features are shared with RIR and PIP Box motifs: Some of the MIP motifs might also superpose on those motifs enabling switching between motif interaction partners. Backbone peptides and the conserved Ser make several H-bonds to orient the motif. fully annotated
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LIG_integrinA1B1_KTS [RK]TS wh0cd7749203 Order Propecia wh0cd7749203 <a href=http://buypropecia2017.com/>Order Propecia</a> wh0cd7749203 <a href=http://buypropecia2017.com/>Order Propecia</a> fully annotated
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LIG_ANKRIN_ANKRA2_1 PxLPx[IL] Xu,2012,3SO8,3V2O,3V2X,3V31,3V30,3UXG,3UZD Sequence-Specific Recognition of a PxLPxL Motif by an Ankyrin Repeatin ANKRA2. Motif is found in HDAC4, HDAC5, HDAC9, megalin, and regulatory factor X, 5 (RFX5). Annotated as LIG_ANK_PxLPxL_1 fully annotated
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DOC_MAPK_RevD_# Garai,2012,
2Y9Q,
3TEI
RevD is the reverse orientation of the MapK docking motif or D motif. It has an amphipathic helical component positioning three hydrophobic residues, a variable spacer and then at least two positively charged residues. Variants of the motif may have preferences for different MapKs such as ERK or p38.
(DOC_MAPK_1)
Annotated as DOC_MAPK_RevD_3 fully annotated
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LIG_G3BP_FGDF_1 ##FG[DE]F[DEST] Panas,2015 Motif in USP10 that binds to G3BP as part of stress granule regulation. The system is hijacked by some viral proteins e.g. Semliki Forest virus nsP3 and HSV ICP8 Annotated as LIG_G3BP_FGDF_1 fully annotated
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LIG_KLC1_TPR_1 [ILMV].W[ED][DN][ES] Konecna,2006
Morgan,2010
Rosa-Ferreira,2011
Pernigo,2013
3ZFW
Motif in calsyntenin binding to TPR (tetratricopeptide repeat) domains of Kinesin Light Chain1 (KLC1. Also used by Vaccinia Virus. Probably general cargo binding motif, often found paired in cargo proteins. Probably only the W is absolutely conserved, followed by the +1 DE position. Elsewhere charge complementarity may involve multiple alternative positions.
Annotated as LIG_KLC1_TPR_1
fully annotated
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LIG_CSL [VILMF]W[VILMF]P 15297877, Wilson,2006, 2FO1 N-terminal motif in Notch, responsible for its interaction with the CSL transcription factor in the nucleus to activate the pathway. Annotated as LIG_CSL_BTD_1. fully annotated
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LIG_PALB2_BRCA2_1 WF..L Oliver,2009,
3EU7
Motif in the BRCA2 N-terminus that binds to PALB2. The interaction is required to bring BRCA2 to nuclear foci and is important for DNA double strand break repair. The helical motif core WF..L enters a hydrophobic pocket on the beta-propeller. Additional residues preceding the core also interact on a shallower part of the surface. The N-terminal region of BRCA2 is highly conserved, implying additional interactions are made. This complicates conservation-based estimation of the motif pattern.
Annoteted as LIG_PALB2_WD40_1
fully annotated
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LIG__UBA3_E1E2_1 [MLI][ILMF].[VILM].{0,4}K Huang,2004
1TT5
Motif in UBC12 (Neddylation E2) N-terminus that binds in a groove of UBA3 in the E1 complex, determining a neddylation specific interaction. The N-terminal region has an overlapping motif that binds the DCNL co-E3 ligase so this peptide segment must be part of a switching mechanism during neddylation. Spacing of the terminal basic residue needs to be assessed from alignments. Also whether arginine at different spacing will replace lysine.

annotated as LIG_UBA3_1
fully annotated
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LIG_PONY_DCNL_1 ^M[ILMF].[IL] Monda,2013
Scott,2011
Huang,2009
4GAO
4GBA
3TDU
N-terminally acetylated motif used during neddylation. When acetylated, NEDD8 E2 ligase N-termini bind the PONY domain of paralogous DCNL1,2,3 NEDD8 co-E3 ligases. Structures of the bound motif available for the NEDD8 E2s UBC12 and UBE2F. The N-terminal region has an overlapping motif that binds the E1 UBA3 so this peptide segment must be part of a switching mechanism during neddylation. Binds in helical conformation so may be possible to extend the motif e.g. to include lysines that make electrostatic interactions but might not be positionally fixed.

annotated as LIG_DCNL_PONY_1
fully annotated
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LIG_LRP6_inhibitor NX[VI] Cheng,2011
Ahn,2011
22589387
Bourhis,2011

3SOV
3SOQ
3SOB
1NPE
2JTK
LRP5/6 are the crucial membrane receptor proteins for Wnt Signalling. These proteins form complex with frizzled receptors and allow binding of Wnt which mediates the canonical Wnt Signalling. Antagonists such as Dickkopf (DKK) and sclerostin (SOST) compete with Wnt protein for binding with LRP5 and LRP6. Binding of antagonists halts the canonical Wnt signaling and presents these antagonists as an important therapeutic target. DKK1 can bind independently on two different sites (2:1).
Constructs with mutations in “NXI” motif (N40A, I42E) show decreased binding.

annotated as LIG_LRP6_Inhibitor_1
fully annotated
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LIG_GSK3_LRPinhibit_1 PPP[ST]P.[ST] Stamos,2014,
4NM5,
4NM7
The protein kinase GSK3 is active by default. Repeating phosphorylated motifs in the LRP5/6 wnt receptors bind as pseudosubstrates, inhibiting the kinase. As a result, the beta-catenin phosphodegron is no longer phosphorylated, stabilising the transcription factor and allowing its transfer into the nucleus. GSK3 also has an auto-inhibitory N-terminal phosphopeptide which is phosphorylated in different regulatory contexts (e.g. insulin signalling) with a somewhat different, less Pro-rich, sequence preference.

annotated as LIG_GSK3_LRP6_1
fully annotated
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LIG_Fzd_KTXXXW KTXXXW 22411803
PMC:3657389
Wong,2003
Punchihewa,2009
Umbhauer,2000

4JKV
The motif is present in C-terminal domain of frizzleds. This motif interacts with PDZ domains of Dishevelled proteins with a low binding affinity. The affinity is affected by the extended regions around motif (N-ter and C-ter both directions). It is known that mutations in this motif lead to disruption of Wnt signalling. This is justified as both Frizzled and Dishevelled are crucial for canonical and non-canonical Wnt signalling pathway. Further this motif is also present in smoothened (SMO) receptors which are having sequence similarity with FZDs. Among the different frizzled types Fz1, Fz2, Fz3, Fz4, and Fz7 have been shown to bind directly with PDZ domain of Dishevelled. The binding of Dishevelled with Fz5 is via a discontinued motif which is spread over C-terminal region of latter. The interaction involves cooperative action of conserved motifs present in third intracellular loop alongwith KTXXXW motif.

annotated as LIG_FZD_DVL_PDZ
fully annotated
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LIG_GBD_WASP_1 [ILV][ILVA]..LM..[ILMV] Sallee,2008, Cheng,2008,2K42 Auto inhibitory motif in WASP and N-WASP that binds the autoinhibitory GTPase binding domain (GBD). E. coli EspF(U) also use the motif to deregulate actin assembly. fully annotated
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LIG_SUMO_Rev_2 [ED].{0,4}[DE].(K)[FLMVI] Impens,2014
Tammsalu,2014
Hendriks,2014
The reverse sumoylation site is less common (about 20% of SUMO sites) than the canonical site. The requirement for a hydrophobic residue adjacent to the modified K may be weaker. MOD_SUMO_rev_2 fully annotated
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LIG_SUFU_Gli_1 [CY]GH[LF} Dunaeva,2003
ZeRuth,2011
responsible for Gli proteins interactions with Sufu. Found in Gli1,2,3 but probably not Gli4. Also found in Glis3 but probably not in Glis1,2. In fly Y is replaced by C. Have not checked animals at higher divergence. LIG_SUFU_1 fully annotated
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LIG_RPA_C_ 1 R[QN][RK].[AL] Mer,2000
Ciccia,2009
1DPU

RPA recognition motif found in DNA repair proteins SMARCAL1, Tipin, UNG2, XPA and AD52 LIG_RPA_C_Fungi, LIG_RPA_C_Insects, LIG_RPA_C_Plants, LIG_RPA_C_Vert fully annotated
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LIG_SPRY_SPSB [DE][IL]NNN Filippakopoulos,2010, 2V24 Motif found in PAR-4/VASA mediating binding to the SPRY domain of the SPSB family of E3 ubiquitin ligases and their orthologue GUSTAVUS LIG_SPRY_1 fully annotated
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Doc_Pex_5 LVAEF Neuhaus,2014

4BXU
LVAEF is a Pex14-binding motif located at the N-terminal domain of the human PTS1 (Peroxisomal targeting signal 1) receptor Pex5. It has been suggested that the motif represents a docking site for cargo loaded receptor. Mutating motif to alanines affects the import of proteins into peroxisomes. Evolutionary conserved consensus sequence of the motif is LVXEF. The motif is not found in plant and yeast Pex5 but is present in Pex5 from a number of filamentous fungi. Binding kinetics of LVAEF motif are faster than the canonical diaromatic pentapeptide motif (WXXX[FY]) present in Pex5. This suggests that site might assist in establishing the first contact of Pex14 with PTS1 receptor. LIG_Pex14_3 fully annotated
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LIG_LIR WxxL or [WYF]xx[LIV] Rozenknop,2011 LC3-interacting region (LIR) might link ubiquitinated substrates that should be degraded to the autophagy modifiers in the autophagosome membrane LIG_LIR_Gen_1; LIG_LIR_Apic_2, LIG_LIR_LC3C_4, LIG_LIR_Nem_3 fully annotated
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LIG_CID_NIM_1 DDDEDgyNPYTl Tudek,2014
2MOW
Motif in Trf4 that binds to the CID domain of Nrd1. Links the TRAMP complex to the NNS complex involved in sn/snoRNA production. NIM acts as a molecular switch, competing for binding with the RNA Pol CTD phosphomotif YSPTSPS. Interaction defined in yeast. Alignment needed to derive the motif conservation in fungi, metazoa etc. Not to be confused with the CNOT1 binding NIM motif. LIG_CID_NIM_1 fully annotated
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DEG_Kelch_KLHL2_1 E.EE.E[AV]DQH Takahashi,2013 WNK kinases are involved in osmotic regulation and may be mutated in certain diseases that show a hypertension phenotype. An Acidic degron motif is highly conserved in vertebrate WNKs and is reported to target them for destruction by the cullin/KLHL2,3 kelch proteins, the latter designated as E3 ligases. WNK kinases disregulated for proper destruction can cause hypertensive disease.
Motif very strongly conserved in 4 vertebrate paralogues. Should look deeper into metazoa for motif definition. DEG_Kelch_KLHL3_1 fully annotated
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DEG_Kelch_KEAP1_1 D.ETGE Padmanabhan,2006, Lo,2006, Lo,2006, 2FLU Oxidative stress response degron motif in the Nrf2 TF binding to the Kelch beta propeller domain in E3 ligase Keap1. A second Nrf2 motif LxxQDxDLG may bind the same Kelch domain with lower affinity. PGAM5 has an NxESGE and is also a Keap1 substrate. DEG_Kelch_Keap1_1 fully annotated
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LIG_APCC_Dbox_3 .R.{2,3}L.{1,3}[LIVM] Hames,2001
11285280
Extended Dbox also tends to have further residues upstream that are required for recognition DEG_APCC_DBOX_1 fully annotated
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Mtr4-binding motif in Air2 GRYFG Falk,2014
4U4C
One of several peptide motifs used in assembly of the TRAMP complex in yeast. Docks the zinc knuckle protein Air1/2 onto the helicase Mtr4. TRAMP is involved in nuclear surveillance of ncRNAs.
fully annotated
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DEG_SPOP_SBC_1 [AVP].S[ST][ST] Zhuang,2009
Zhang,2009
3IVQ
The SPOP Cullin E3 ligase recognizes an unusual ST-rich peptide motif in substrate proteins. The phosphorylated site does not bind SPOP, offering possibilities for PTM regulation. Substrates include GLI3 and MacroH2A. fully annotated
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DOC_Cks1_1 [PLFWY][^P](T)P. McGrath,2013, Koivomagi,2013, 4LPA Cks1 co-regulates CDK activity. A subset of pTP sites can be bound in CDK substrates or other regulators. CDK site targeting becomes more precise than with cyclin docking alone. Only described so far in the yeast experimental system but Cks1 homologues are found in e.g. vertebrates too. fully annotated
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Doc_PP2A_KARD_1 LS.I[IML]E.S....T Suijkerbuijk,2012,Kruse,2013,Xu,2013 The card motif in BUBR1 recruits the phosphatase PP2A during cell cycle. This is important for mitotic progression. The motif is considered to be triply phosphorylated to bind PP2A.
fully annotated
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Doc_GSK3_Axin_1 P[^P][^P]Fa[^P][^P]Li[^P][^P]L[^P][^P][VIL] Dajani,2003
1O9U
Helical motif in Axin protein docks GSK3beta into the Axin-scaffolded complexes. Docked GSK3beta can mark beta-catenin for destruction. The FRAT helical motif binds the same surface but the details are different. fully annotated
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LIG_MTR4_Trf4_1 NxDFIx[FL] Falk,2014
Losh,2015
4U4C
One of several peptide motifs used in assembly of the TRAMP complex in yeast. Docks the poly(A)polymerase Trf4/5 by beta augmentation onto the helicase Mtr4. TRAMP is involved in nuclear surveillance of ncRNAs.
Motif pattern should be possible to define for metazoan equivalent with core EQxDF[IL]P fully annotated
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LIG_ALG2 PPYP.{1,4}YP Suzuki,2008, 2ZNE motif in Alix that binds to ALG-2 in a calcium-dependent manner (allosteric opening of hydrophobic pocket on ALG-2); similar sequence present in annexin A7 and A11, and in TSG101 fully annotated
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LIG_AIM [WY]..[ILV] Noda,2010,3dow,2zzp,2zjd,2zpn Atg8-family interacting motif (AIM) found in Atg19, p62, Atg4B and Calreticulin, involved in autophagy related processes fully annotated
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LIG_GABARAP W.FL Thielmann,2009
Mohrluder,2007
17916189
3DOW
GABAA receptor binding to clathrin and calreticulin. possibly linked to trafficking fully annotated
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DCK_dephos_PP1_2 R..Q[VIL][KR].[YW] Terrak,2004,Hendrickx,2009, 1S70 Docking motif, referred to as the MyPhoNe motif, for PP1 phosphatase found in Myosin phosphatase-targeting subunit 1. fully annotated
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LIG_CNOT1_NIM_1 F..W.DY..L Bhandari,2014, 4CQO The NIM motif (Not1 Interacting Motif) is conserved in the vertebrate RNA-binding paralogues, Nanos1, -2, -3. It binds the SHD domain of CNOT1, thereby recruiting the CCR4-NOT deadenylase complex. Nanos is a classical developmental regulator affecting posterior pattern formation in Drosophila. It is an RNA-binding protein affecting post-transcriptional mRNA regulation. The CCR4-NOT deadenylase complex catalyses the removal of poly(A) tails. The Nanos/CCR4-NOT interaction therefore modulates translational repression. fully annotated
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LIG_PP2B_2 .L.VP Rodriguez,2009, Roy,2009, Liu,2001, 10202017, Martinez-Martinez,2006, Park,2000, Dougherty,2009, Mehta,2009, Blumenthal,1986, Grigoriu,2013,
4F0Z
Secondary, lower affinity(?), docking motif for the calcium-activated phosphatase Calcineurin/PP2B. Found in NFATc1-4, KSR2, PRKAR2A and yeast RCN1. ("PVIVIT") is the other Calcineurin binding motif. High affinity motifs may have a large hydrophobic residue preceding the L. The solved motif structure has lysine replacing proline. Binds activated form of Calcineurin; requires both catalytic CNA and regulatory CNB subunits for binding (binding site was identified in silico as hydrophobic cleft formed at interface of preassembled CNA and CNB and confirmed with the solved structure). fully annotated
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FUN_N-end_rule_pathway Tasaki,2007 N-terminal ubiquitin mediated destruction system. May be ancient. Might not be a single motif but a combination of post translational modifications. fully annotated
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TRG_ER_diArg_2 .RR. 14527949 Generic di-arginine ER retention motif fully annotated
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LIG_TRAF2_3 P.Q.[ST] 12917691
Ye,1999
Ye,1999
1CZY
1QSC
1CZZ
Slight variant of LIG_TRAF motifs already in ELM. fully annotated
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FUN_RANK P[VILF]QE 16260781 Motif in cytosolic part of RANK (TNFR11A) reported to mediate osteoclast formation, survival and function. Also found in TNFR5. Specific subset of LIG_TRAF2 with improved motif definition. PVQE is absolutely conserved twice in RANK and once in TNFR5. The reported PFQE is unconserved. Therefore the motif is probably an exact match to PVQE

Ligand domain is not known yet?
fully annotated
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LIG_WD40_WDR5win_1 G[GASC]AR....[FLYM] Dharmarajan,2012,
18829457,
18829459,
16829960,
3UVN,
3UVL
The Win motif has a turn of helix with an Arg residue that binds deep into the wD40 domain axis. Found in WDR5-interacting proteins including SET1A and MLL2 Small sidechains precede the R. Pro should be disfavoured at several positions of the motif due to backbone H-bonding requirements. A preference for a hydrophobic residue is found +5 of the R. fully annotated
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LIG_WD40_WDR5_2 .VDV[TV] Odho,2010
2XL2
The VDV motif is found in RbBP5 and interacts with an edge cleft of the WD40 domain in WDR5.
This interaction surface is different from the canonical axial site (in this case bound by the Win motif). RbBP5 is found in a number of chromatin complexes including SET1 and MLL.
Core motif may be preceded by several negatively charged residues. The core D does not directly bind WDR5 but makes an internal charged interaction that is probably important for the peptide geometry.

fully annotated
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DCK_dephos_PP1_3 [GS]IL[RK] Wakula,2003 Docking motif, referred to as the SILK motif, for PP1 phosphatase found in NIPP1 fully annotated
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LIG_CASK_CID_1 E.[IV]W[IV].R Stafford,2011 Docking motif in Caskin1, Mint1 and TIAM1 that binds to the CASK hub protein involved in brain, synapse, cell polarity. fully annotated
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LIG_N_degron_UBR_type1 ^[RKH][^P] Matta-Camacho,2010,Choi,2010, 3NY1, 3NIT Primary N-terminal basic degron. Likes hydrophobics in second position. Lysine binds with the highest affinity (~20uM). N-degrons are N-terminal proteosomal degradation targeting motifs recognised by UBR domains of the Ubiquitin recognin (UBR) family. Several N-degrons are known, defined as primary (type 1 & type 2), secondary and tertiary. fully annotated
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LIG_N_degron_UBR_type2 ^[FLWYI] Tasaki,2007 Primary N-terminal bulky hydrophobic degron. N-degrons are N-terminal proteosomal degradation targeting motifs recognised by UBR domains of the Ubiquitin recognin (UBR) family. Several N-degrons are known, defined as primary (type 1 & type 2), secondary and tertiary. fully annotated
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LIG_N_degron_UBR_secondary ^[DEC] Tasaki,2007 Secondary N-degron, arginylated (addition of an N-terminal arginine) by Arg-tRNA-tranferase. Cysteine must first be oxidised into Cys-sulfinic acid before arginylation. Once arginylated the motif is recognised as a type1 N-degron. N-degrons are N-terminal proteosomal degradation targeting motifs recognised by UBR domains of the Ubiquitin recognin (UBR) family. Several N-degrons are known, defined as primary (type 1 & type 2), secondary and tertiary fully annotated
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LIG_N_degron_UBR_tertiary ^[NQ] Tasaki,2007 Tertiary N-degron, deamidated by N-terminal amidohydrolase. Deamidation creates the secondary destabilising N-terminal residues Asp and Glu, which in turn are arginylated (addition of an N-terminal arginine) by Arg-tRNA-tranferase to create a primary N-degron. N-degrons are N-terminal proteosomal degradation targeting motifs recognised by UBR domains of the Ubiquitin recognin (UBR) family. Several N-degrons are known, defined as primary (type 1 & type 2), secondary and tertiary. fully annotated
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LIG_TNK_1 R..PDG 22153076,Guettler,2011 Tankyrase 1 & 2 (TNKS, TNKS2) bind to a common set of proteins including IRAP, TAB182 and FBP17, all of whom share this common motif. Annotated as LIG_TNKBM_1 fully annotated
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LIG_APCC_Cbox DR[YF]IP.R Schwab,2001 motif required for association with APC/C, conserved in Cdc20-related proteins annotated as LIG_APCC_Cbox_1 / LIG_APCC_Cbox_2 fully annotated
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LIG_APCC_#R_1 .[LM]R$ Sedgwick,2013, Hayes,2006 Some proteins interact with APC/C via C-terminal LR or MR motifs. These include Nek2A and Kif18A. The MR motif in Nek2A allows it to be destroyed by APC/C in a checkpoint independent manner annotated as LIG_APCC_TPR_1 fully annotated
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LIG_APCC_IR_1 .IR$ Burton,2005,Passmore,2003,Vodermaier,2003 The C-terminal IR motif anchors CDC20 and CDH1 D/KEN box adaptors as well as APC10 to the main APC/C complex. Recognised by a groove in TPR repeats. annotated as LIG_APCC_TPR_1 fully annotated
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LIG_SCF_TIR1 GWPPV 15295098
Ramos,2001
Parry,2006
Tan,2007
2P1Q
A degron motif found in plants responsible for the degradation of members of the Aux/IAA family of transcriptional repressors fully annotated
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LIG_PAM2_2 W..EF.PG..W.... Jinek,2010,Kozlov,2010, 2X04, 3KTP binding motif in GW182 family proteins for binding with PABC domain of PABP1, essential for microRNA-mediated translation repression and deadenylation fully annotated
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LIG_PAM2 [FPLV][^P][IPVTA].A..F.P Kozlov,2004,Albrecht,2004,Kozlov,2010 PABC/MLLE2-binding motifs involved in translational regulation. fully annotated
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LIG_SCF_COI1 RR..L..FL Chini,2007
Sheard,2010
3OGM
Thines,2007
Katsir,2008
Gfeller,2010
a degron found in plants associated with the Jasmonate family of transcription repressors. fully annotated
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LIG_NBox_RRM_1 Cukier,2010 Ala-rich amphipathic helical motif in FBP and homologues binding to the helical side of FIR RRM2 which has a shallow hydrophobic face. Part of FIR mediated c-myc transcriptional control. fully annotated
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LIG_MYND_2 PPPLI Liu,2007, 2ODD Motif that mediates the interaction between MYND domain of AML1/ETO and co-repressors SMRT and N-CoR. fully annotated
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LIG_MYND_PHD2_1 P.LE Song,2013 Variant MYND binding motif found in the HSP90 co-chaperones p23 and FKBP38 interacting with PHD2 MYND domain Interaction is part of HIF1-alpha hydroxyproline oxygene sensing system fully annotated
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MOD_phos_NEK2 [FLM][^P][^P]([ST])[^DEP][HR] Alexander,2011 Canonical motif phosphorylated by NEK2 MOD_NEK2_1, MOD_NEK2_2 fully annotated
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LIG_CEP55 GPP...Y Lee,2008, 3E1R motif in Alix and TSG101 that interacts with coiled coil in CEP55; motif overlaps with motif for binding to ALG-2 fully annotated
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TRG_ER_diArg_1 R.{0, 1}R Michelsen,2005 ER retention/retrieving signal found in ER membrane proteins (cytoplasmic side) should replace current TRG_ER_diArg_1 fully annotated
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LIG_SCF_SKP2 Hao,2005 Complex phosphopeptide motif binding to the assembled dimer of Skp2 and Cks1 (SCF components), in the ubiquitin degradation process. annotated as LIG_SCF_Skp2-Cks1_1 fully annotated
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LIG_PIKK_1 [DEN][DEN].{2,3}[ILMVA][DEN][DEN]L.{0,20}$ Falck,2005 Docking motif for PIKK kinases family found in DNA damage proteins Nbs1, ATRIP and XRCC5. alias DCK_phos_PIKK_1 fully annotated
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LIG_eIF4E_1 Y....L[VILMF] Fierro-Monti,2006 Motif present in some interacting partners of eIF4E. annotated as LIG_eIF4E_1 fully annotated
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LIG_eIF4E_2 Y.PP.[ILMV]R Shih,2008 Mediates binding to the dorsal surface of eIF4E. Found in DDX3, eIF-3G and eIF-2A annotated as LIG_eIF4E_2 fully annotated
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MOD_LATS_1 H.R..[ST] Zhao,2007 Mammalian tumour suppressors LATS1 and 2 are AGC group kinases involved in the Hippo pathway. Similar kinases are conserved in other Eukaryotes. Known substrates YAP1 and WWTR1 (TAZ) have multiple HxRxxS motifs that are phosphorylated by the LATS kinases. Thus these kinases appear to have a target specificity that is distinct from other AGC group kinases. annotated as MOD_LATS_1 fully annotated
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LIG_SUMO_SBM V.[VI][VI] Song,2004, Hecker,2006, Berndt,2009 Motif reported to bind SUMO present in RanBP2, PML, among cothers. annotated as LIG_SUMO_SBM_1 and LIG_SUMO_SBM_2 fully annotated
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CLV_Separin S[HILMV][DE].GR[RKS] Sullivan,2001 Recognition site for cleavage by Caspase-like protease Separin. annotated as CLV_Separin_Metazoa and CLV_Separin_Fungi fully annotated
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LIG_RhoGAP_OCRL_1 F...H..[ILVFY] PDB:Pirruccello,2011,3QIS F&H motif mediates binding to the RhoGAP domain of OCRL. Found in Ses1, Ses2 and APPL1. annotated as LIG_OCRL_FandH_1 fully annotated
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LIG_Pex3P_1 L..LL...L..F Sato,2010 Large induced hydrophobic helix mediating binding to the Pex3p protein, found in Pex19p. annotated as TRG_PEX_3 fully annotated
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Lig_CAP-Gly_2 W[KR][ED]GCY$ van der Vaart,2011,3RDV C-terminal Tyr-based motif in SLAIN2 that binds the CAP-Gly motif of CLIP-170 as part of MT regulation by +TIP interaction networks. Lig_CAP-Gly_CLIP170_2 fully annotated
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CLV_Caspase3-7 D..D[AGS] 12107159 Caspase-3/Caspase-7 cleavage motif. fully annotated
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LIG_SCF_Cks1_1 .E.(T)P. Hao,2005, 2AST Phosphodegron in P27kip1 which must be targeted for destruction by SCF ubiquitination to allow the cell cycle progression fully annotated
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LIG_HCF-1 [ED]H.Y Luciano,2003 HCF-binding motif, to bind to a six-bladed β-propeller domain at the N terminus of HCF-1 fully annotated
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LIG_RB_pocket [IL]..L[YF] Liu,2007,Xiao,2003 Binding to the E2f binding pocket between the Rb-A and Rb-B domains fully annotated
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LIG_SPAK-OSR1 RF.V Villa,2007 Docking motif in substrates of OSR1 and SPAK kinases that binds to the CCT domain. fully annotated
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LIG_Integrin_isoDGR NGR Spitaleri,2008 Integrin aVB3 binding motif in the 5th type I repeat of fibronectin. Aspargine deamidation at an NGR peptide generates the functional isoDGR binding motifs. Binds with comparable affinity to the canonical RGD peptide that binds the same site. fully annotated
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LIG_Actin_WH2_1 [ILMV][ILMV]..I.{4,7}L[KR][KR][ILMVT] Paunola,2002,2A3Z,2A40,2A41,2D1K,2VCP,3MN5,3MN7 Long actin binding motif, probably too large to be defined as an ELM but if we put LIG_Actin_RPEL_1 in then this will also be entered. fully annotated
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LIG_Actin_RPEL_1 L..[KR][IL]..R[PQ]...[ED]L..[RK].[ILMV][ILMV] Mouilleron,2008,2V52 Bipartite helical motif mediating binding to the subdomain 1-3 hydrophobic cleft and a ledge on subdomain 3 of G-actin. Probably to large to be defined as an ELM but may be seen as a bipartite motif with possible unknown monopartite motif-containing binding partners binding one of the two interfaces. fully annotated
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LIG_PIF F..F or F..F([ST]) Biondi,2004 Binding motif in PDK1, PKA, PKG, PKC etc. AGC kinase pockets, usually in cis, except in PDK1 where there it is a trans docking motif. fully annotated
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Please cite: ELM — the eukaryotic linear motif resource in 2020. (PMID:31680160)

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